DOCSLIB.ORG

Tonic and Spillover Inhibition of Granule Cells Control Information Flow Through Cerebellar Cortex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tonic and Spillover Inhibition of Granule Cells Control Information Flow Through Cerebellar Cortex View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron, Vol. 33, 625–633, February 14, 2002, Copyright 2002 by Cell Press Tonic and Spillover Inhibition of Granule Cells Control Information Flow through Cerebellar Cortex Martine Hamann, David J. Rossi, the fraction of granule cells excited by mossy fiber input and David Attwell1 to the cerebellum and, thus, to increase cerebellar infor- Department of Physiology mation storage capacity (Marr, 1969; Tyrrell and Will- University College London shaw, 1992). However, the relative importance of tonic Gower Street versus mossy fiber driven inhibition and their effect on London, WC1E 6BT the input-output relationship of the cerebellar cortex United Kingdom have not been studied, largely because until recently, it was not possible to block inhibition of granule cells without also blocking inhibition of Purkinje cells. Summary Here, we show that both spillover and tonic inhibition of adult granule cells are mediated largely by receptors We show that information flow through the adult cere- that are blocked by furosemide and insensitive to diaze- bellar cortex, from the mossy fiber input to the Purkinje pam and neurosteroids. We quantify the relative impor- cell output, is controlled by furosemide-sensitive, di- tance of tonic inhibition and of the direct and spillover azepam- and neurosteroid-insensitive GABAA recep- components of synaptically evoked inhibition. Finally, tors on granule cells, which are activated both tonically we demonstrate that tonic and spillover inhibition of and by GABA spillover from synaptic release sites. granule cells play a major role in controlling information Tonic activation of these receptors contributes a flow through the cerebellar cortex. 3-fold larger mean inhibitory conductance than GABA released synaptically by high-frequency stimulation. Results Tonic and spillover inhibition reduce the fraction of granule cells activated by mossy fiber input, generat- Tonic Inhibition of Granule Cells ing an increase of coding sparseness, which is pre- In cerebellar slices from adult rats, applying the GABAA dicted to improve the information storage capacity of receptor blocker bicuculline to granule cells whole-cell the cerebellum. clamped at Ϫ60 mV with electrodes containing isotonic Ϫ Cl (ECl ϭ 0 mV) produced an outward current shift of Introduction 42 Ϯ 4 pA, reflecting the suppression of a tonic conduc- tance of 700 Ϯ 60 pS generated by GABAA receptors Transmitter spilling out of the synaptic cleft can generate (Figure 1A). Similar results were seen with the GABAA ␮ a current in distant neurons if their receptors have a blockers GABAzine (Figure 1G) and picrotoxin (100 M, sufficiently high affinity (EC Ϸ 1 ␮M) to respond to two cells; data not shown). The current was not reduced 50 Ϯ ϭ ␮ the low concentration of transmitter reaching them; for (0.6% 2.9%, p 0.85) by TTX (1 M, Figures 1A and example, NMDA receptors in the case of glutamate 1C; cf. Kaneda et al., 1995; Wall and Usowicz, 1997) or 2ϩ Ϯ ϭ (Isaacson, 1999) or GABA receptors containing the ␣ by removing external Ca (9.6% 3.8%, p 0.09, A 6 2ϩ subunit (Rossi and Hamann, 1998). High-affinity recep- replaced by Mg and 2 mM EGTA; Figures 1B and 1C). Thus, the tonic conductance is not activated by GABA tors may also generate a current even in the absence released by action potentials or Ca2ϩ influx. of synaptic transmitter release if the background trans- mitter concentration maintained by transporters is in the Tonic Inhibition Is Mediated by Furosemide- low micromolar range that activates the receptors. Tonic Sensitive, Diazepam- and Neurosteroid- activation by low background levels of transmitter may Insensitive GABA Receptors occur for hippocampal and cerebellar NMDA receptors A In adult granule cells, most GABA receptors contain ␣ (Sah et al., 1989; Rossi and Slater, 1993) and in adult A 1 or ␣ subunits together with ␤ or ␤ and ␥ or ␦ subunits cerebellar granule cells that show an action potential- 6 2 3 2 (Laurie et al., 1992a; Quirk et al., 1994; Wisden et al., independent tonic GABA receptor conductance (Kaneda A 1996; Nusser et al., 1998, 1999; Pirker et al., 2000). Furo- et al., 1995; Tia et al., 1996a; Brickley et al., 1996; Wall semide (100 ␮M) inhibits receptors containing ␣6 sub- and Usowicz, 1997). units (with an IC of 10–40 ␮M), but not ␣ -containing In cerebellar granule cells, the molecular identity, cel- 50 1 receptors lacking ␣6 subunits (IC50 Ͼ 3 mM; Korpi et al., lular location, and functional role of the GABAA receptors 1995; Sigel and Baur, 2000), irrespective of the presence mediating spillover and tonic inhibition are uncertain. of ␥2 or ␦ subunits (Korpi and Lu¨ ddens, 1997; Thomp- Pharmacology shows that the receptors mediating spill- son et al., 1999). Furosemide produced an outward cur- ␣ over inhibition contain 6 subunits (Rossi and Hamann, rent (Figures 1D and 1G) that was 58% Ϯ 4% of the 1998), but the receptors’ other subunits are unknown. current produced by bicuculline in the same cells. No ␣ Mice lacking 6 subunits lack the tonic conductance current was produced by furosemide in bicuculline (Fig- (Brickley et al., 2001), but this need not imply that tonic ures 1D and 1G). Furosemide did not generate a current ␣ inhibition is due to receptors containing 6 subunits be- by blocking KCl cotransporters (Payne, 1997) and alter- cause of side effects of the ␣ knockout (see Discussion). Ϫ 6 ing [Cl ]i since the KCl cotransport blocker bumetanide Inhibition of granule cells has been postulated to reduce did not affect the membrane current (Figures 1E and 1G) when applied at a dose (220 ␮M) producing the as 100 ␮M (%80ف) 1Correspondence: [email protected] same inhibition of KCl transporters Neuron 626 Figure 1. Tonic Inhibition of Adult Granule Cells Is by Furosemide-Sensitive, Diazepam- Insensitive GABAA Receptors (A) Response of a granule cell at Ϫ60 mV (ECl ϭ 0 mV, so GABAA currents are inward) to bicuculline (40 ␮M) and to bicuculline in the presence of TTX (1 ␮M). Dotted lines show zero current. (B) Response to bicuculline in normal solution and in zero Ca2ϩ solution. (C) Mean bicuculline-evoked currents in the presence and absence of TTX (four cells) and of Ca2ϩ (four cells). (D) Response to furosemide (100 ␮M) and to furosemide in the presence of bicuculline (40 ␮M). (E) Response to furosemide and to bumeta- nide (220 ␮M). (F) Response to diazepam (0.5 ␮M) and to bicuculline. (G) Mean current shifts at Ϫ60 mV evoked by bicuculline (bic; 40 ␮M, 45 cells), GABAzine (10 ␮M, n ϭ 9), furosemide (furo; 100 ␮M, n ϭ 18), furosemide in bicuculline (n ϭ 4), bumetanide (bum; 220 ␮M, n ϭ 12), and diaz- epam (dz; 0.5 ␮M, n ϭ 7). Traces are filtered at 2 Hz, so individual spontaneous IPSCs are not visible. furosemide (Payne, 1997). Furthermore, as shown be- (Zhu et al., 1996; Wohlfarth et al., 2002; see Discussion). low, furosemide did not affect the holding current of In adult granule cells, the neurosteroid THDOC (3␣,21- Golgi, Purkinje, stellate, or basket cells that do not ex- dihydroxy-5␣-pregnan-20-1, 0.1 ␮M) generated an in- press ␣6 subunits (Laurie et al., 1992a), nor did it generate ward current (11 Ϯ 3 pA) corresponding to a 34% Ϯ 5% a current in granule cells from 6-day-old rats (n ϭ 5, potentiation of the bicuculline-sensitive tonic current in data not shown), at which age there is little expression the same cell (Figures 2A and 2C), which was abolished of ␣6 subunits (Laurie et al., 1992b). Diazepam (0.5 ␮M), by bicuculline (40 ␮M, n ϭ 4) and reduced 43% Ϯ 10% which potentiates 2- to 3-fold the response of ␣1-con- by furosemide (100 ␮M, n ϭ 5; data not shown). By taining receptors, but not of ␣6-containing receptors contrast, in granule cells in 6-day-old rats that do not (Saxena and MacDonald, 1996; Sigel and Baur, 2000), yet express ␦ subunits (Laurie et al., 1992b) and show did not affect the tonic current in adult granule cells no tonic current (Brickley et al., 1996; Wall and Usowicz, (Figures 1F and 1G), although it did potentiate (nonspillo- 1997), THDOC potentiated the response to 5 ␮M exoge- ver) synaptic responses mediated by ␣1-containing re- nous GABA by 84% Ϯ 15% (Figures 2B and 2C). Simi- ceptors in these cells (Figure 2H). Thus, the tonic current larly, pregnenolone sulfate (1 ␮M) did not affect the tonic in mature granule cells is generated exclusively by furo- GABAA current of adult granule cells (Figures 2D and semide-sensitive, diazepam-insensitive GABAA recep- 2F) but did inhibit the response of 6-day-old granule tors; i.e., receptors containing ␣6 subunits (see Dis- cells to 5 ␮M GABA (Figures 2E and 2F). Thus, compared cussion). to GABA-evoked currents in young animals, the tonic In granule cells, ␣6 subunits coassemble with ␥2 and/or current in adult granule cells is insensitive to neuroste- ␦ subunits (Nusser et al., 1998; Quirk et al., 1994; Jech- roids. The likely receptor subunit composition conferring linger et al., 1998). Neurosteroids modulate GABAA re- this pharmacological profile (furosemide-sensitive, diaz- ceptors, but, in receptors containing ␣6 or ␣1 subunits, epam- and neurosteroid-insensitive) is assessed in the this modulation is altered by the presence of ␦ subunits Discussion section. Tonic and Spillover Inhibition 627 Figure 2. Inhibition of Granule Cells by Neu- rosteroid-Insensitive GABAA Receptors (A) Potentiation of the tonic current in an adult (P35) granule cell by THDOC (0.1 ␮M); re- sponse to bicuculline shows size of tonic cur- rent; ECl ϭ 0 mV. (B) Potentiation by THDOC of the response of a young (P6) granule cell to GABA (5 ␮M).
Load more

Recommended publications
  • Amnestic Concentrations of Sevoflurane Inhibit Synaptic
    Anesthesiology 2008; 108:447–56 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Amnestic Concentrations of Sevoflurane Inhibit Synaptic Plasticity of Hippocampal CA1 Neurons through ␥-Aminobutyric Acid–mediated Mechanisms Junko Ishizeki, M.D.,* Koichi Nishikawa, M.D., Ph.D.,† Kazuhiro Kubo, M.D.,‡ Shigeru Saito, M.D., Ph.D.,§ Fumio Goto, M.D., Ph.D.࿣ Background: The cellular mechanisms of anesthetic-induced for surgical procedures do not have recollection of ac- amnesia are still poorly understood. The current study exam- tually being awake despite being awake and cooperative ined sevoflurane at various concentrations in the CA1 region of during the procedure.1 Galinkin et al.2 compared sub- rat hippocampal slices for effects on excitatory synaptic trans- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/108/3/447/366512/0000542-200803000-00017.pdf by guest on 29 September 2021 mission and on long-term potentiation (LTP), as a possible jective, psychomotor, cognitive, and analgesic effects of mechanism contributing to anesthetic-induced loss of recall. sevoflurane (0.3% and 0.6%) with those of nitrous oxide Methods: Population spikes and field excitatory postsynaptic at equal minimum alveolar concentrations (MACs) in potentials were recorded using extracellular electrodes after healthy volunteers. They found that sevoflurane pro- electrical stimulation of Schaffer-collateral-commissural fiber inputs. Paired pulse facilitation was used as a measure of pre- duced a greater degree of amnesia and psychomotor synaptic effects of the anesthetic. LTP was induced using tetanic impairment than did an equal MAC of nitrous oxide but stimulation (100 Hz, 1 s). Sevoflurane at concentrations from had no analgesic actions.
    [Show full text]
  • Picrotoxin-Like Channel Blockers of GABAA Receptors
    COMMENTARY Picrotoxin-like channel blockers of GABAA receptors Richard W. Olsen* Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, CA 90095-1735 icrotoxin (PTX) is the prototypic vous system. Instead of an acetylcholine antagonist of GABAA receptors (ACh) target, the cage convulsants are (GABARs), the primary media- noncompetitive GABAR antagonists act- tors of inhibitory neurotransmis- ing at the PTX site: they inhibit GABAR Psion (rapid and tonic) in the nervous currents and synapses in mammalian neu- system. Picrotoxinin (Fig. 1A), the active rons and inhibit [3H]dihydropicrotoxinin ingredient in this plant convulsant, struc- binding to GABAR sites in brain mem- turally does not resemble GABA, a sim- branes (7, 9). A potent example, t-butyl ple, small amino acid, but it is a polycylic bicyclophosphorothionate, is a major re- compound with no nitrogen atom. The search tool used to assay GABARs by compound somehow prevents ion flow radio-ligand binding (10). through the chloride channel activated by This drug target appears to be the site GABA in the GABAR, a member of the of action of the experimental convulsant cys-loop, ligand-gated ion channel super- pentylenetetrazol (1, 4) and numerous family. Unlike the competitive GABAR polychlorinated hydrocarbon insecticides, antagonist bicuculline, PTX is clearly a including dieldrin, lindane, and fipronil, noncompetitive antagonist (NCA), acting compounds that have been applied in not at the GABA recognition site but per- huge amounts to the environment with haps within the ion channel. Thus PTX major agricultural economic impact (2). ͞ appears to be an excellent example of al- Some of the other potent toxicants insec- losteric modulation, which is extremely ticides were also radiolabeled and used to important in protein function in general characterize receptor action, allowing and especially for GABAR (1).
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • Exploring the Activity of an Inhibitory Neurosteroid at GABAA Receptors
    1 Exploring the activity of an inhibitory neurosteroid at GABAA receptors Sandra Seljeset A thesis submitted to University College London for the Degree of Doctor of Philosophy November 2016 Department of Neuroscience, Physiology and Pharmacology University College London Gower Street WC1E 6BT 2 Declaration I, Sandra Seljeset, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I can confirm that this has been indicated in the thesis. 3 Abstract The GABAA receptor is the main mediator of inhibitory neurotransmission in the central nervous system. Its activity is regulated by various endogenous molecules that act either by directly modulating the receptor or by affecting the presynaptic release of GABA. Neurosteroids are an important class of endogenous modulators, and can either potentiate or inhibit GABAA receptor function. Whereas the binding site and physiological roles of the potentiating neurosteroids are well characterised, less is known about the role of inhibitory neurosteroids in modulating GABAA receptors. Using hippocampal cultures and recombinant GABAA receptors expressed in HEK cells, the binding and functional profile of the inhibitory neurosteroid pregnenolone sulphate (PS) were studied using whole-cell patch-clamp recordings. In HEK cells, PS inhibited steady-state GABA currents more than peak currents. Receptor subtype selectivity was minimal, except that the ρ1 receptor was largely insensitive. PS showed state-dependence but little voltage-sensitivity and did not compete with the open-channel blocker picrotoxinin for binding, suggesting that the channel pore is an unlikely binding site. By using ρ1-α1/β2/γ2L receptor chimeras and point mutations, the binding site for PS was probed.
    [Show full text]
  • 268 Part 522—Implantation Or Injectable Dosage Form
    § 520.2645 21 CFR Ch. I (4–1–18 Edition) (ii) Indications for use. For the control 522.82 Aminopropazine. of American foulbrood (Paenibacillus 522.84 Beta-aminopropionitrile. larvae). 522.88 Amoxicillin. 522.90 Ampicillin injectable dosage forms. (iii) Limitations. The drug should be 522.90a Ampicillin trihydrate suspension. fed early in the spring or fall and con- 522.90b Ampicillin trihydrate powder for in- sumed by the bees before the main jection. honey flow begins, to avoid contamina- 522.90c Ampicillin sodium. tion of production honey. Complete 522.144 Arsenamide. treatments at least 4 weeks before 522.147 Atipamezole. main honey flow. 522.150 Azaperone. 522.161 Betamethasone. [40 FR 13838, Mar. 27, 1975, as amended at 50 522.163 Betamethasone dipropionate and FR 49841, Dec. 5, 1985; 59 FR 14365, Mar. 28, betamethasone sodium phosphate aque- 1994; 62 FR 39443, July 23, 1997; 68 FR 24879, ous suspension. May 9, 2003; 70 FR 69439, Nov. 16, 2005; 73 FR 522.167 Betamethasone sodium phosphate 76946, Dec. 18, 2008; 75 FR 76259, Dec. 8, 2010; and betamethasone acetate. 76 FR 59024, Sept. 23, 2011; 77 FR 29217, May 522.204 Boldenone. 17, 2012; 79 FR 37620, July 2, 2014; 79 FR 53136, 522.224 Bupivacaine. Sept. 8, 2014; 79 FR 64116, Oct. 28, 2014; 80 FR 522.230 Buprenorphine. 34278, June 16, 2015; 81 FR 48702, July 26, 2016] 522.234 Butamisole. 522.246 Butorphanol. § 520.2645 Tylvalosin. 522.275 N-Butylscopolammonium. 522.300 Carfentanil. (a) Specifications. Granules containing 522.304 Carprofen. 62.5 percent tylvalosin (w/w) as 522.311 Cefovecin.
    [Show full text]
  • Sample Chapter
    LCMS_Chap09 (JB-D) 8/5/06 3:14 pm Page 193 9 LC-MS in doping control Detlef Thieme Introduction adjacent fields with similar analytical prospects, like veterinary residue control (predominantly dealing with identification of growth promoters Definition of doping in various matrices), forensic sciences (the major- ity of doping-relevant substances are scheduled Doping analysis comprises a diversity of sub- as controlled substances in most countries), stance classes with different pharmaceutical and environmental analysis (e.g. steroids in waste chemical properties. Therefore, the discussion of water) or clinical chemistry (e.g. due to the the suitability of liquid chromatography-mass increasing relevance of steroid hormone replace- spectrometry (LC-MS) in doping analysis needs ment therapy). to distinguish various categories. This chapter describes the key fields of appli- According to its formal definition, a doping cation of LC-MS in routine doping control (i.e. violation in sports can be caused by various screening analysis, confirmation and quantifica- events, e.g.: tion of positive results) extra to particular • the detection of a prohibited substance or research activities. The latter are focused on the metabolites or markers of that substance (as intended technical improvements (e.g. extension defined by the recent document [1] of the of detection time windows, reduction of turn- World Anti-Doping Agency [WADA]) in the around times and costs) of conventional analyti- athlete’s specimen cal procedures and, in particular, on the detection • the use of prohibited substances or methods of prohibited substances that cannot be ade- • possession or trafficking prohibited substances quately identified so far (e.g.
    [Show full text]
  • Toxicological and Pharmacological Profile of Amanita Muscaria (L.) Lam
    Pharmacia 67(4): 317–323 DOI 10.3897/pharmacia.67.e56112 Review Article Toxicological and pharmacological profile of Amanita muscaria (L.) Lam. – a new rising opportunity for biomedicine Maria Voynova1, Aleksandar Shkondrov2, Magdalena Kondeva-Burdina1, Ilina Krasteva2 1 Laboratory of Drug metabolism and drug toxicity, Department “Pharmacology, Pharmacotherapy and Toxicology”, Faculty of Pharmacy, Medical University of Sofia, Bulgaria 2 Department of Pharmacognosy, Faculty of Pharmacy, Medical University of Sofia, Bulgaria Corresponding author: Magdalena Kondeva-Burdina ([email protected]) Received 2 July 2020 ♦ Accepted 19 August 2020 ♦ Published 26 November 2020 Citation: Voynova M, Shkondrov A, Kondeva-Burdina M, Krasteva I (2020) Toxicological and pharmacological profile of Amanita muscaria (L.) Lam. – a new rising opportunity for biomedicine. Pharmacia 67(4): 317–323. https://doi.org/10.3897/pharmacia.67. e56112 Abstract Amanita muscaria, commonly known as fly agaric, is a basidiomycete. Its main psychoactive constituents are ibotenic acid and mus- cimol, both involved in ‘pantherina-muscaria’ poisoning syndrome. The rising pharmacological and toxicological interest based on lots of contradictive opinions concerning the use of Amanita muscaria extracts’ neuroprotective role against some neurodegenerative diseases such as Parkinson’s and Alzheimer’s, its potent role in the treatment of cerebral ischaemia and other socially significant health conditions gave the basis for this review. Facts about Amanita muscaria’s morphology, chemical content, toxicological and pharmacological characteristics and usage from ancient times to present-day’s opportunities in modern medicine are presented. Keywords Amanita muscaria, muscimol, ibotenic acid Introduction rica, the genus had an ancestral origin in the Siberian-Be- ringian region in the Tertiary period (Geml et al.
    [Show full text]
  • Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor
    The Journal of Neuroscience, January 15, 1997, 17(2):625–634 Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor Shinya Ueno,1 John Bracamontes,1 Chuck Zorumski,2 David S. Weiss,3 and Joe Henry Steinbach1 Departments of 1Anesthesiology and 2Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and 3University of Alabama at Birmingham, Neurobiology Research Center and Department of Physiology and Biophysics, Birmingham, Alabama 35294-0021 Anesthetic drugs are known to interact with GABAA receptors, bicuculline only partially blocked responses to pentobarbital. both to potentiate the effects of low concentrations of GABA and These observations indicate that the blockers do not compete to directly gate open the ion channel in the absence of GABA; with alphaxalone or pentobarbital for a single class of sites on the however, the site(s) involved in direct gating by these drugs is not GABAA receptor. Finally, at receptors containing a1b2(Y157S)g2L known. We have studied the ability of alphaxalone (an anesthetic subunits, both bicuculline and gabazine showed weak agonist steroid) and pentobarbital (an anesthetic barbiturate) to directly activity and actually potentiated responses to alphaxalone. These activate recombinant GABAA receptors containing the a1, b2, and observations indicate that the blocking drugs can produce allo- g2L subunits. Steroid gating was not affected when either of two steric changes in GABAA receptors, at least those containing this mutated b2 subunits [b2(Y157S) and b2(Y205S)] are incorporated mutated b2 subunit. We conclude that the sites for binding ste- into the receptors, although these subunits greatly reduce the roids and barbiturates do not overlap with the GABA-binding site.
    [Show full text]
  • DIURETICS Diuretics Are Drugs That Promote the Output of Urine Excreted by the Kidneys
    DIURETICS Diuretics are drugs that promote the output of urine excreted by the Kidneys. The primary action of most diuretics is the direct inhibition of Na+ transport at one or more of the four major anatomical sites along the nephron, where Na+ reabsorption takes place. The increased excretion of water and electrolytes by the kidneys is dependent on three different processes viz., glomerular filtration, tubular reabsorption (active and passive) and tubular secretion. Diuretics are very effective in the treatment of Cardiac oedema, specifically the one related with congestive heart failure. They are employed extensively in various types of disorders, for example, nephritic syndrome, diabetes insipidus, nutritional oedema, cirrhosis of the liver, hypertension, oedema of pregnancy and also to lower intraocular and cerebrospinal fluid pressure. Therapeutic Uses of Diuretics i) Congestive Heart Failure: The choice of the diuretic would depend on the severity of the disorder. In an emergency like acute pulmonary oedema, intravenous Furosemide or Sodium ethacrynate may be given. In less severe cases. Hydrochlorothiazide or Chlorthalidone may be used. Potassium-sparing diuretics like Spironolactone or Triamterene may be added to thiazide therapy. ii) Essential hypertension: The thiazides usually sever as primary antihypertensive agents. They may be used as sole agents in patients with mild hypertension or combined with other antihypertensives in more severe cases. iii) Hepatic cirrhosis: Potassium-sparing diuretics like Spironolactone may be employed. If Spironolactone alone fails, then a thiazide diuretic can be added cautiously. Furosemide or Ethacrymnic acid may have to be used if the oedema is regractory, together with spironolactone to lessen potassium loss. Serum potassium levels should be monitored periodically.
    [Show full text]
  • Uniform Classification Guidelines for Foreign Substances and Recommended Penalties Model Rule
    DRUG TESTING STANDARDS AND PRACTICES PROGRAM. Uniform Classification Guidelines for Foreign Substances And Recommended Penalties Model Rule. January, 2018 (V.13.4) Ó ASSOCIATION OF RACING COMMISSIONERS INTERNATIONAL – 2018. Association of Racing Commissioners International 1510 Newtown Pike, Lexington, Kentucky, United States www.arci.com Page 1 of 61 Preamble to the Uniform Classification Guidelines of Foreign Substances The Preamble to the Uniform Classification Guidelines was approved by the RCI Drug Testing and Quality Assurance Program Committee (now the Drug Testing Standards and Practices Program Committee) on August 26, 1991. Minor revisions to the Preamble were made by the Drug Classification subcommittee (now the Veterinary Pharmacologists Subcommittee) on September 3, 1991. "The Uniform Classification Guidelines printed on the following pages are intended to assist stewards, hearing officers and racing commissioners in evaluating the seriousness of alleged violations of medication and prohibited substance rules in racing jurisdictions. Practicing equine veterinarians, state veterinarians, and equine pharmacologists are available and should be consulted to explain the pharmacological effects of the drugs listed in each class prior to any decisions with respect to penalities to be imposed. The ranking of drugs is based on their pharmacology, their ability to influence the outcome of a race, whether or not they have legitimate therapeutic uses in the racing horse, or other evidence that they may be used improperly. These classes of drugs are intended only as guidelines and should be employed only to assist persons adjudicating facts and opinions in understanding the seriousness of the alleged offenses. The facts of each case are always different and there may be mitigating circumstances which should always be considered.
    [Show full text]
  • RAC-GWVI: Research Alerts—Pubmed Citations for August 21 to 28, 2018 1
    RAC-GWVI: Research Alerts—PubMed Citations for August 21 to 28, 2018 1 GULF WAR ILLNESS Neurotoxicity in acute and repeated organophosphate exposure. Naughton SX1, Terry AV Jr2. Toxicology. 2018 Aug 22. pii: S0300-483X(18)30264-6. doi: 10.1016/j.tox.2018.08.011. PMID: 30144465. [Epub ahead of print] The term organophosphate (OP) refers to a diverse group of chemicals that are found in hundreds of products worldwide. As pesticides, their most common use, OPs are clearly beneficial for agricultural productivity and the control of deadly vector-borne illnesses. However, as a consequence of their widespread use, OPs are now among the most common synthetic chemicals detected in the environment as well as in animal and human tissues. This is an increasing environmental concern because many OPs are highly toxic and both accidental and intentional exposures to OPs resulting in deleterious health effects have been documented for decades. Some of these deleterious health effects include a variety of long-term neurological and psychiatric disturbances including impairments in attention, memory, and other domains of cognition. Moreover, some chronic illnesses that manifest these symptoms such as Gulf War Illness and Aerotoxic Syndrome have (at least in part) been attributed to OP exposure. In addition to acute acetylcholinesterase inhibition, OPs may affect a number of additional targets that lead to oxidative stress, axonal transport deficits, neuroinflammation, and autoimmunity. Some of these targets could be exploited for therapeutic purposes. The purpose of this review is thus to: 1) describe the important uses of organophosphate (OP)-based compounds worldwide, 2) provide an overview of the various risks and toxicology associated with OP exposure, particularly long-term neurologic and psychiatric symptoms, 3) discuss mechanisms of OP toxicity beyond cholinesterase inhibition, 4) review potential therapeutic strategies to reverse the acute toxicity and long term deleterious effects of OPs.
    [Show full text]
  • Mechanisms of Sevoflurane-Induced Myocardial Preconditioning In
    Anesthesiology 2003; 99:27–33 © 2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Mechanisms of Sevoflurane-induced Myocardial Preconditioning in Isolated Human Right Atria In Vitro Alexandra Yvon, B.Sc.,* Jean-Luc Hanouz, M.D, Ph.D.,† Benoît Haelewyn, B.Sc.,* Xavier Terrien, B.Sc.,* Massimo Massetti, M.D.,‡ Gérard Babatasi, M.D., Ph.D.,‡ André Khayat, M.D.,§ Pierre Ducouret, Ph.D.,࿣ Henri Bricard, M.D.,# Jean-Louis Gérard, M.D., Ph.D.** Background: The authors examined the role of adenosine postischemic contractile function,5–7 and metabolic triphosphate–sensitive potassium channels and adenosine A 7 1 function. Although the mechanisms involved in anes- receptors in sevoflurane-induced preconditioning on isolated thetic preconditioning remain incompletely understood, human myocardium. Methods: The authors recorded isometric contraction of hu- protein kinase C, adenosine triphosphate–sensitive po- man right atrial trabeculae suspended in oxygenated Tyrode’s tassium (KATP) channels, and adenosine A1 receptors Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/99/1/27/408853/0000542-200307000-00008.pdf by guest on 02 October 2021 solution (34°C; stimulation frequency, 1 Hz). In all groups, a seem to play a key role.1,2,5,6 However, recent studies 30-min hypoxic period was followed by 60 min of reoxygenation. suggest that volatile anesthetic–induced myocardial pre- Seven minutes before hypoxia reoxygenation, muscles were ex- posed to 4 min of hypoxia and 7 min of reoxygenation or 15 min conditioning may be dependent on species and experi- 5,8 of sevoflurane at concentrations of 1, 2, and 3%. In separate mental models.
    [Show full text]